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Background Sleep problems are common in autistic children and adversely impact daytime functioning. The Children's Sleep Habits Questionnaire (CSHQ) [39] was developed from a community-based sample of children and has validated a cut-off score of 41. Katz et al. [50] developed an abbreviated 23-item four-factor version of the CSHQ, which may be useful when assessing sleep in autistic children. However, a cut-off value has not yet been developed. Objective: Our objective was to develop and validate a cut-off for the CSHQ-autism total score in order to identify sleep problems among autistic children. We hypothesized that the derived cut-off value for the CSHQ-autism would perform better than the original CSHQ cut at 41 on validation in a sample of autistic children. Methods Age-specific cut-off values were developed and validated using receiver operating characteristic analysis. Results The derived cut-off values for the CSHQ-autism total score were 34, 35, 33, and 35 for the 2–3, 4–10, 11–17, and 2–17 years age groups, respectively. On validation, all cut-off values performed with moderate to high sensitivity (76.6–82.4%) and moderate specificity (69.1–75.5%), while the original CSHQ cut at 41 had high sensitivity (89.9–93.0%) but low specificity (42.6–57.7%). Using McNemar's tests, the CSHQ-autism had significantly higher specificity but lower sensitivity than the original CSHQ cut at 41 in all age groups. Conclusions The CSHQ-autism cut-off values performed better overall than the original CSHQ cut at 41 in a sample of autistic children. The CSHQ-autism cut-off can help identify sleep problems among autistic children.

Background Insomnia and low iron stores are common in children with autism spectrum disorders, and low iron stores have been associated with sleep disturbance. Methods We performed a randomized placebo-controlled trial of oral ferrous sulfate to treat insomnia in children with autism spectrum disorders and low normal ferritin levels. Twenty participants who met inclusion criteria and whose insomnia did not respond to sleep education were randomized to 3 mg/kg/day of ferrous sulfate (n = 9) or placebo (n = 11) for three months. Results Iron supplementation was well tolerated, and no serious adverse events were reported. Iron supplementation improved iron status (+18.4 ng/mL active versus −1.6 ng/mL placebo, P = 0.044) but did not significantly improve the primary outcome measures of sleep onset latency (−11.0 minutes versus placebo, 95% confidence interval −28.4 to 6.4 minutes, P = 0.22) and wake time after sleep onset (−7.7 minutes versus placebo, 95% confidence interval −22.1 to 6.6 min, P = 0.29) as measured by actigraphy. Iron supplementation was associated with improvement in the overall severity score from the Sleep Clinical Global Impression Scale (−1.5 points versus placebo, P = 0.047). Changes in measures of daytime behavior did not differ between groups. Conclusion This trial demonstrated no improvement in primary outcome measures of insomnia in subjects treated with ferrous sulfate compared with placebo. Interpretation was limited by low enrollment.

Sleep problems are common in autistic children and adversely impact daytime functioning. Knowledge of predictive factors could help with treatment and prevention of these problems. This study aimed to determine predictors of sleep problems among young autistic children. Study cohorts consisted of autistic children aged 2–5 years who did not have sleep problems at a first visit and had sleep measure data available at a subsequent visit. Sleep problems for five study cohorts were defined by different methods: Children’s Sleep Habits Questionnaire with two cutoff scores (41 and 48; cohort n = 101 and 204, respectively), Children’s Sleep Habits Questionnaire–autism derived cutoff score (35; n = 188), and parent- (n = 205) or clinician- (n = 252) report. Separate predictive models of sleep problems were developed in each cohort using multivariable logistic regression with final model predictors determined by backward elimination selection. Model performance was evaluated. Two of the five models had both adequate discrimination and calibration performance predicting (1) Children’s Sleep Habits Questionnaire score ⩾ 48 and (2) Children’s Sleep Habits Questionnaire–autism score ⩾ 35. In both models, self-injurious behavior, sensory issues, dental problems, and lower primary caregiver education level were significant risk factors of future sleep problems. These predictors may be useful in helping clinicians provide prevention strategies or early intervention for children who are at a higher risk of developing sleep problems. Lay abstract Sleep problems are common in autistic children and negatively impact daytime functioning. A method for predicting sleep problems could help with treatment and prevention of such problems. This study aimed to determine predictors of sleep problems among young autistic children. Study participants consisted of autistic children aged 2–5 years who did not have sleep problems at a first visit (Autism Treatment Network Registry) and had sleep data available at a subsequent visit (Registry Call-Back Assessment study). Sleep problems for five study cohorts of children were defined by different methods, including parent questionnaires and parent- or clinician-report of sleep problems. We found that self-injurious behavior, sensory issues, dental problems, and lower primary caregiver education level were significant risk factors of future sleep problems. These predictors may help clinicians provide prevention or earlier treatment for children who are at risk of developing sleep problems.

Background: Angelman syndrome (AS) is a rare neurogenetic disorder present in approximately 1/12,000 individuals and characterized by developmental delay, cognitive impairment, motor dysfunction, seizures, gastrointestinal concerns, and abnormal electroencephalographic background. AS is caused by absent expression of the paternally imprinted gene UBE3A in the central nervous system. Disparities in the management of AS are a major problem in preparing for precision therapies and occur even in patients with access to experts and recognized clinics. AS patients receive care based on collective provider experience due to limited evidence-based literature. We present a consensus statement and comprehensive literature review that proposes a standard of care practices for the management of AS at a critical time when therapeutics to alter the natural history of the disease are on the horizon. Methods: We compiled the key recognized clinical features of AS based on consensus from a team of specialists managing patients with AS. Working groups were established to address each focus area with committees comprised of providers who manage >5 individuals. Committees developed management guidelines for their area of expertise. These were compiled into a final document to provide a framework for standardizing management. Evidence from the medical literature was also comprehensively reviewed. Results: Areas covered by working groups in the consensus document include genetics, developmental medicine, psychology, general health concerns, neurology (including movement disorders), sleep, psychiatry, orthopedics, ophthalmology, communication, early intervention and therapies, and caregiver health. Working groups created frameworks, including flowcharts and tables, to help with quick access for providers. Data from the literature were incorporated to ensure providers had review of experiential versus evidence-based care guidelines. Conclusion: Standards of care in the management of AS are keys to ensure optimal care at a critical time when new disease-modifying therapies are emerging. This document is a framework for providers of all familiarity levels.

One of the most significant revisions to the ICH E6 GCP Guideline in the last 20 years was issued in November 2016, adopted by the EMA in December 2016 and by the FDA as a Guidance Document in March 2018. The new section on Quality Management requires the implementation of a systematic approach for managing risks throughout the course of a clinical study. The addendum also emphasizes appropriate sponsor oversight. Currently available risk management solutions are fairly elaborate, having been developed for and adopted mainly by larger companies. Small to medium size companies find these solutions too complex and not easily adaptable. In this paper, we present a simple but robust toolkit for clinical study risk management for small to medium sized organizations in order to facilitate compliance. The toolkit consists of customizable templates for the following: Clinical Risk Management SOP; Clinical Risk Management Plan; Vendor Oversight SOP; Vendor Oversight Plan; and Clinical Risk Log. The tools were prepared by the DIA GCP-QA Community members and presented at the 2018 DIA Annual Meeting in Boston.

BACKGROUND: Sleep problems can impact daytime behavior, quality of life, and overall health. We compared sleep habits in young children with autism spectrum disorder (ASD) and other developmental delays and disorders and in children from the general population (POP). METHODS: We included 2- to 5-year-old children whose parent completed all items on the Children’s Sleep Habits Questionnaire (CSHQ) in a multisite case-control study: 522 children with ASD; 228 children with other developmental delays and disorders with autism spectrum disorder characteristics (DD w/ASD); 534 children with other developmental delays and disorders without autism spectrum disorder characteristics (DD w/o ASD); and 703 POP. Multivariable analysis of variance compared CSHQ mean total score (TS) and subscale scores between groups. Logistic regression analysis examined group differences by using TS cutoffs of 41 and 48. Analyses were adjusted for covariates. RESULTS: Mean CSHQ TS for children in each group: ASD (48.5); DD w/ASD (50.4); DD w/o ASD (44.4); and POP (43.3). Differences between children with ASD and both children with DD w/o ASD and POP were statistically significant. Using a TS cutoff of 48, the proportion of children with sleep problems was significantly higher in children in the ASD group versus DD w/o ASD and POP groups (adjusted odds ratios [95% confidence intervals]: 2.12 [1.57 to 2.87] and 2.37 [1.75 to 3.22], respectively). CONCLUSIONS: Sleep problems are more than twice as common in young children with ASD and DD w/ASD. Screening for sleep problems is important in young children to facilitate provision of appropriate interventions.

Background In autism, poor sleep begins in early childhood, varies in severity and is associated with behavioural difficulties. We examined relationships between sleep and behaviour in young children with autism and no, mild/typical or severe/atypical sleep problems to determine behavioural profiles that may differentiate sleep problem severity. Method Parents of children with autism aged 2- to 5-years reported on their child’s sleep behaviour (CSHQ), including additional written descriptions of sleep behaviours. Children were then classified as good sleepers or as having mild/typical or severe/atypical sleep problems using National Sleep Foundation guidelines and current sleep literature. The three sleep groups were compared on autistic severity (ADOS), cognition (Mullen Scales of Early Leaning) and behaviour (BASC-3). Results Parents of 46 children aged 24- to 71-months participated. The severe/atypical sleep group were more likely to have multiple severe sleep difficulties. The sleep groups did not differ on autism severity or cognition. The BASC-3 withdrawal subscale differentiated severe problem sleepers from the other groups, while BASC-3 inattention differentiated problem sleepers from good sleepers. The severe/atypical sleep problem group also had more overall behaviour problems than good sleepers Conclusions Social withdrawal and multiple, severe sleep difficulties may underlie difficulties in treating poor sleep in some autistic children, suggesting that an individualised approach to treatment is needed to address severe sleep concerns. Early detection and intervention for poor sleep may reduce or prevent significant sleep and behavioural concerns continuing into later childhood. Sleep interventions that include targeting attention and withdrawal behaviours may assist in in this regard.

Background Sleep problems are common in individuals with ASD. This study examined the relationships between bedtime consistency, cognitive functioning, comorbid diagnoses, intervention, demographics and sleep duration in children with ASD. Method Cross-sectional data from 1683 children with ASD in the 2016 and 2017 National Survey of Children's Health were analyzed. The sample was 80 % male, 46 % non-Hispanic white, and mean age was 10.5 (SD 4.1) years. All data were parent report. Multiple linear regression was performed. Results ASD severity was associated with shorter sleep duration, and bedtime consistency was associated with longer sleep duration. Age moderated the effects of both bedtime consistency and ADD/ADHD on sleep duration. Both the positive effect of bedtime consistency and the negative effect of ADD/ADHD on sleep duration became less pronounced with age. Conclusion Although the challenges related to sleep and behavior may differ by age of the child, bedtime consistency could be a good target to improve sleep duration for all children with ASD. Future studies, especially longitudinal studies, on sleep habits and sleep hygiene, in conjunction with other measures of sleep patterns (e.g., night wakings) and correlates of sleep problems, may provide further evidence for the importance of good sleep practices and guide sleep treatment in children with ASD.

The DIA's Good Clinical Practice and Quality Assurance Community (DIA GCP/QA) created a working group to develop templates for a protocol deviation standard operating procedure (SOP) and protocol deviation handling plan (PDHP).The working group consisted of QA auditors, data managers, statisticians, and clinical monitors from several pharmaceutical companies, academia, and independent auditing firms. Various examples of standard operating procedures, data handling plans, and auditing plans were examined, and the core elements extracted into the initial PD SOP and PDHP templates. The draft templates were presented at a workshop at the DIA 51st Annual Meeting held in June 2015 in Washington, DC, and feedback was incorporated. The workshop came at the heels of a previously published position paper, "The Lifecycle and Management of Protocol Deviations."The PD SOP and the PDHP templates are presented in this article. They are a starting point, and each company will need to modify to suit its individual needs.This article expands on the position paper to include concrete tools for the management of protocol deviations, including best practices for detection, classification, mitigation, and management of protocol deviations with a goal to reduce the impact on subject safety and data integrity.

Clinical trials are designed to evaluate the efficacy, safety, or other characteristics associated with medical products. Trials are usually complex and require a large group of professionals to follow a clinical trial protocol, standard operating procedures, and study-specific manuals, guidelines, and plans. Clinical trial protocols prospectively describe the background and rationale for conducting the trial, the objectives of the trial, the trial design, the equipment to be used, the procedures to be performed, and the statistical methods on how the trial data are to be analyzed. Deviations from the protocol can result in harm to subjects, biased or inaccurate results, and possible rejection of all or part of the trial data by the sponsor or regulatory authorities. Despite preventive efforts, protocol deviations are likely to occur in most trials. This position paper proposes a common definition of protocol deviations and recommends best practices for their detection, classification, and management as part of their life cycle, with a goal of reducing their impact on subject safety and data integrity. The information contained herein is drawn globally from industry experts within the DIA Good Clinical Practice and Quality Assurance community, an industry-wide survey, and presentations with discussions at various industry meetings.

OBJECTIVES: Constipation and insomnia are not consistently identified and treated in children with autism spectrum disorder (ASD) despite their high prevalence and deleterious impact in this population. To standardize care, a constipation practice pathway and an insomnia practice pathway were previously developed by Autism Treatment Network clinicians. Our objective was to implement and refine these practice pathways in clinical settings. METHODS: Eleven Autism Treatment Network sites participated in a Learning Collaborative (ie, multidisciplinary quality improvement team) and chose to implement either the constipation or insomnia practice pathway in the clinical setting. Families set intervention goals (eg, increase stool frequency, decrease nighttime awakenings) before treatment. Each site began implementation with 1 patient and then increased implementation by factors of 5. Before each increase, the Learning Collaborative evaluated progress and refined the practice pathways. Process improvement was measured primarily by duration until goal attainment and by percentage of families who meet their goals. RESULTS: Across sites, 82 children with ASD and constipation and 101 children with ASD and insomnia were managed. Difficulties with intervention adherence and communication between providers and families were reported and were subsequently improved with parallel refinements to both practice pathways. The most notable modification was incorporating a goal-setting session in which families generated their own intervention goals (ie, family-driven goals). In this quality improvement initiative, 75% of families met at least 1 constipation or insomnia goal, with the median time to improvement being 6 weeks. CONCLUSIONS: By integrating a family-centered approach into the standardization of care, constipation and insomnia practice pathways may improve engagement, adherence, and management of medical conditions in children with ASD.

Sleep disturbance is common in children with autism, resulting in a great need for effective treatments. To evaluate treatments for sleep disturbance in this population, it is critical to understand the relationship between measures of sleep captured by parent report and objective measures. The Children's Sleep Habits Questionnaire (CSHQ) and actigraphy-measured data from 80 children with autism and sleep-onset delay were evaluated. Reported problems with sleep-onset delay were concurrent with sleep duration problems in 66% of children, night wakings in 72% of children, and bedtime resistance in 66% of children; 38% of children were reported to have problems with all CSHQ insomnia domains. Actigraphy-measured sleep duration was correlated with estimates using CSHQ-reported bed and wake times.

Missing Data in Clinical Trials Forum Loews Philadelphia Hotel, Philadelphia, PA, USA, 16–17 March 2015 Missing data, defined as values not available that would have been meaningful for analysis if they were observed, are commonplace in academic, government and industry run clinical trials. However, this data loss can result in an inadequate basis for study inferences. In 2014, multiple US FDA advisory committees challenged the quantity of missing data and the conclusions drawn from their study outcomes, resulting in approval delays or rejection of product registration. The Missing Data in Clinical Trials Forum invited experts from academia, government and industry to explore methods to avoid missing data by design, and present on tools to detect and rectify missing data during the trial. Statistical methodology to impute or model data missing at random, or not at random, was also discussed.

Background Sleep difficulties in children with autism spectrum disorders (ASD) have been well-established. Aims To develop a model to predict sleep problems in children with ASD. Methods and procedures A sample of children in the Autism Speaks-Autism Treatment Network (ATN) registry without parent-reported sleep problems at baseline and with sleep problem (yes/no) data at first annual followup was randomly split into training (n = 527) and test (n = 518) samples. Model predictors were selected using the training sample, and a threshold for classifying children at risk was determined. Comparison of the predicted and true sleep problem status of the test sample yielded model performance measures. Outcomes and results In a multivariable model aggressive behavior among children with no sleep problems reported at baseline was associated with having more sleep problems at the first annual follow-up visit. This model performed in the test sample with high sensitivity and accurate prediction of low risk. Conclusions and implications Among children with ASD aggressive behavior independently predicts sleep problems. The model's high sensitivity for identifying children at risk and its accurate prediction of low risk can help with treatment and prevention of sleep problems. Further data collection may provide better prediction through methods requiring larger samples.

The current study describes the development and psychometric properties of a new measure targeting sensitivity to change of core autism spectrum disorder (ASD) symptoms, the Autism Impact Measure (AIM). The AIM uses a 2-week recall period with items rated on two corresponding 5-point scales (frequency and impact). Psychometric properties were examined using a large sample (n = 440) of children with ASD enrolled in the Autism Treatment Network. The exploratory factor analysis indicated four factors and resulted in a 25-item questionnaire with excellent overall model fit. Test-retest reliability, cross-informant reliability, and convergent validity with other measures of ASD symptoms and overall functioning were strong. The AIM is a reliable and valid measure of frequency and impact of core ASD symptoms.

Loews Philadelphia Hotel, Philadelphia, PA, USA, 15–16 November 2012 The US FDA’s critical path initiative is a national strategy to drive innovation in the scientific processes, through which medical products are developed, evaluated and manufactured. Launched in 2004, and followed in 2006 by the Critical Path Opportunities List, it lists several areas where technology and systems could improve the accuracy of tests that predict the safety and efficacy of potential medical products. Adaptive clinical trial design is one of the major components of the critical path, and in 2010, the FDA issued its draft Guidelines. The Next Generation of Trial Design Innovation Conference had invited several industry experts, and the focus was to explore strategies, methods and logistical considerations for flexible trial designs at the study, product and portfolio level.

To pilot a clinician-based outcome measure that provides complementary information to objective measures and parent-based questionnaires for insomnia in children with autism spectrum disorders (ASD).The authors developed a Pediatric Sleep Clinical Global Impressions Scale (CGI). Questions included (1) the child's ability to fall asleep and remain sleeping independently (i.e., apart from parents); (2) bedtime resistance; (3) sleep onset delay; (4) night awakening; (5) parental satisfaction with their child's current sleep patterns; (6) family functioning as affected by their child's current sleep patterns; and (7) clinician's overall concern with the child's sleep. After refining the instrument through the evaluation of vignettes by ASD and sleep experts, the authors piloted the Pediatric Sleep CGI in a 12-week randomized trial of iron supplementation in children with ASD. Clinicians completed Pediatric Sleep CGIs and structured sleep histories, parents completed the Children's Sleep Habits Questionnaire (CSHQ), and children wore actigraphy watches.In repeated measures models, the Pediatric Sleep CGI and CSHQ were correlated for sleep onset delay (r = .66, p.001), night wakings (r = .40, p.001), and total score (r = .29, p.001). The CGI-S sleep onset delay and actigraphy sleep onset delay scores (r = .75, p = .0095) were also correlated. The overall CGI-S showed improvement with therapy (p = .047).The Pediatric Sleep CGI shows promise in measuring clinician-rated outcomes in pediatric insomnia in children with ASD. Larger samples will be necessary to examine reliability, validity, and measure to change, as well as applicability to other populations with pediatric insomnia.

Background Minimally verbal (MV) children with autism spectrum disorder (ASD) are often assumed to be profoundly cognitively impaired and excluded from analyses due to challenges completing standardized testing protocols. A literature aimed at increasing understanding of this subgroup is emerging; however, the many methods used to define MV status make it difficult to compare studies. Understanding how different instruments and definitions used to identify MV children affect sample composition is critical to advance research on this understudied clinical population. Method The MV status of 1,470 school-aged children was defined using five instruments commonly used in ASD research. MV sample composition was compared across instruments. Analyses examined the proportion of overlap across MV subgroups and the extent to which child characteristics varied across MV subgroups defined using different definitions or combinations of measures. Results A total of 257 children were classified as MV on at least one instrument. Proportion of overlap between definitions ranged from 3% to 100%. The stringency of definition (i.e. few-to-no vs. some words) was associated with differences in cognitive and adaptive functioning; more stringent definitions yielded greater consistency of MV status across instruments. Cognitive abilities ranged from profoundly impaired to average intelligence; 16% had NVIQ ≥ 70. Approximately half exhibited verbal skills commensurate with nonverbal cognitive ability, whereas half had verbal abilities significantly lower than their estimated NVIQ. Conclusions Future studies of MV children must carefully consider the methods used to identify their sample, acknowledging that definitions including children with ‘some words’ may yield larger samples with a wider range of language and cognitive abilities. Broadly defined MV samples may be particularly important to delineate factors interfering with language development in the subgroup of children whose expressive impairments are considerably below their estimated nonverbal cognitive abilities.

OBJECTIVES: Sleep difficulties are common in children with autism spectrum disorders, with wide-ranging effects on the child’s daytime behavior. We reviewed data within our Autism Speaks Autism Treatment Network Registry to determine the prevalence of sleep difficulties and patterns of medication use. METHODS: Data from 1518 children ages 4 to 10 years were analyzed to determine the number of children documented to have sleep difficulties by parent-completed questionnaires and clinician-completed forms and how these findings related to the use of sleep medications. RESULTS: The Children’s Sleep Habits Questionnaire total score was ≥41 (associated with clinically significant sleep problems in past research) in 71% of children. The prevalence of sleep diagnoses was less frequent (30% of children aged 4–10 years; P < .0001). Medications for sleep were prescribed in 46% of 4- to 10-year-olds given a sleep diagnosis. The most common medication used for sleep was melatonin followed by α-agonists, with a variety of other medications taken for sleep (anticonvulsants, antidepressants, atypical antipsychotics, and benzodiazepines). Children taking medications for sleep had worse daytime behavior and pediatric quality of life than children not taking sleep medications. CONCLUSIONS: Parent concerns about sleep may not be reflected in the information gathered during a clinic visit, supporting the need to develop screening practice pathways for sleep in autism spectrum disorders. Furthermore, many medications taken for sleep have adverse effects, supporting the need for evidence-based interventions in this population.

The purpose of this study was to assess the efficacy and safety of bevacizumab plus cetuximab with or without gemcitabine in patients with advanced pancreatic adenocarcinoma. Patients with locally advanced or metastatic pancreatic adenocarcinoma, previously untreated, were randomized to bevacizumab (10 mg/kg q2w) plus cetuximab (400/250 mg/m(2) initial/weekly), either with (Arm A) or without (Arm B) gemcitabine (1000 mg/m(2) weekly × 3 of 4 weeks). Tumor assessments were performed q8w. Primary study endpoint was progression-free survival (PFS). Sixty-one patients were randomized to Arm A (n = 30) or Arm B (n = 31). Median treatment duration was 9 weeks in Arm A and 8 weeks in Arm B (range, 2.0-40.4). Patients in Arm A had median PFS and overall survival values of 3.55 months and 5.41 months, respectively, compared to 1.91 months and 4.17 months in Arm B. The study closed early due to lack of sufficient efficacy in both treatment arms. Although both regimens were well tolerated, patients treated with gemcitabine experienced more grade 3-4 toxicities, including proteinuria and thromboembolic events. The combination of cetuximab and bevacizumab did not result in promising activity with or without gemcitabine, suggesting that a strategy of dual EGFR/VEGF inhibition in pancreatic cancer does not warrant further development. To our knowledge, this is one of the first trials to evaluate a completely noncytotoxic regimen in the first-line treatment of advanced pancreatic cancer. (ClinicalTrials.gov number, NCT00326911).

Sleep disturbances are a well-established problem in autism. Sleep issues can result in problems at home in the evening. Also, poor sleep can result in fatigue and irritability during the daytime, resulting in other potential problems. How sleep disorders are assessed and the best empirical methods to do so are the subject of this chapter.

BACKGROUNDThe purpose of the current study was to evaluate the relationships among sleep problems and daytime behaviors in a large, well-defined cohort of children with autism spectrum disorder (ASD).METHODSOut of a registry population of 3452 children with ASDs, a subset of 1193 children aged 4 to 10 years of age from 14 centers across the country was used to evaluate the relationship between varying levels of sleep problems and daytime behavior. Measures included Children’s Sleep Habits Questionnaire, Vineland Adaptive Behavior Scales, Survey Interview Form, Second Edition, and Child Behavior Checklist. Multiple analysis of covariance was used to assess the association between sleep and behavior.RESULTSResults suggest that sleep problems, as identified by parent report by use of the Children’s Sleep Habits Questionnaire, have a negative relationship with daytime behavior. More specifically, children with ASDs and sleep problems had more internalizing and externalizing behavior problems, as measured by the Child Behavior Checklist, and poorer adaptive skill development, as measured by the Vineland Adaptive Behavior Scales, than children with ASDs and no sleep problems. Children with moderate to severe sleep problems had greater behavior difficulties, but not necessarily poorer adaptive functioning, than children with mild to moderate sleep problems. Both preschool- and school-aged children demonstrated a negative relationship between behavior and sleep, whereas the relationship between sleep and adaptive functioning was much more variable.CONCLUSIONSThese results suggest that, although sleep has a negative relationship with internalizing and externalizing behavior, it may have a different relationship with the acquisition of adaptive skills.

Purpose: This study aimed to determine a maximum tolerated dose (MTD) and recommended dose for disease-directed studies of necitumumab (IMC-11F8), a fully human IgG1 monoclonal antibody directed at the epidermal growth factor receptor, and to characterize the safety profile, pharmacokinetics, preliminary antitumor activity, and immunogenicity of necitumumab. Experimental Design: Patients with advanced solid malignancies were treated with 100 to 1,000 mg (flat dosing) necitumumab followed by a 2-week pharmacokinetics sampling period, before beginning 6-week cycles of therapy. Results: Sixty patients received necitumumab weekly (29 patients) or every other week (31 patients). Two patients receiving 1,000 mg every 2 weeks experienced dose-limiting toxicities (DLT; grade 3 headache), accompanied by grade 3 nausea and vomiting in one patient. Occurring hours after the initial dose, these DLTs established 800 mg as the MTD. Mild dose-related skin toxicity was the most common drug-related toxicity (80%). One patient in each arm experienced grade 3 acneform rash, which responded to oral antibiotics and topical therapy. Toxicity was similar on both schedules. Necitumumab exhibited saturable elimination and nonlinear pharmacokinetics. At 800 mg (both arms), its half-life was approximately 7 days. All patients treated with ≥600 mg necitumumab achieved target trough concentrations (≥40 μg/mL). Antibodies against necitumumab were not detected. Partial response and stable disease were experienced by 2 and 16 patients, respectively. Conclusion: Well tolerated, necitumumab is associated with preliminary evidence of antitumor activity, and achieves biologically relevant concentrations throughout the dosing period. The recommended dose of necitumumab for further clinical development is 800 mg (flat dose) weekly or every 2 weeks based on the clinical setting. Clin Cancer Res; 16(6); 1915–23

The objective of this study was to establish a withdrawal period for flunixin in milk by quantifying 5-hydroxyflunixin, the marker residue, in bovine milk as a function of time, following intravenous treatment of lactating dairy cows with flunixin-N-methyl glucamine (Banamine or Finadyne). Lactating dairy cows were dosed on three consecutive days at 2.2 mg of flunixin free acid/kg of body weight/day. Milk was collected twice daily and assayed using a liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) procedure. The method was validated at concentrations in the range 0.5-250 ppb. The concentrations for 5-hydroxyflunixin measured 12 h after the last administration of drug ranged from 1.56 to 40.6 ppb for all cows. Milk concentrations for 5-hydroxyflunixin were used to establish withdrawal periods of 36 h using guidelines established by the U.S. Food and Drug Administration/Center for Veterinary Medicine and 24 h using guidelines established by the European Medicinal Evaluation Agency/Committee on Veterinary Medicinal Products.

Florfenicol, a broad-spectrum antibiotic, is being developed for veterinary application as an oral concentrate intended for dilution with drinking water. When a drug product is dosed via drinking water in a farm setting, a number of variables, including pH, chlorine content, hardness of the water used for dilution, and container material, may affect its stability, leading to a decrease in drug potency. The stability of florfenicol after dilution of Florfenicol Drinking Water Concentrate Oral Solution, 23 mg/mL, with drinking water was studied. A stability-indicating, validated liquid chromatographic method was used to evaluate florfenicol stability at 25 degrees C at 5, 10, and 24 h after dilution. The results indicate that florfenicol is stable under a range of simulated field conditions, including various pipe materials and conditions of hard or soft and chlorinated or nonchlorinated water at low or high pH. Significant degradation (10%) was observed only for isolated combinations in galvanized pipes. Analysis indicated that the florfenicol concentration in 8 of the 12 water samples stored in galvanized pipes remained above 90% of the initial concentration (100 mg/L) for 24 h after dilution.

Plasma and skin concentrations of orbifloxacin (Orbax tablets, Schering-Plough Animal Health) were assessed in 14 clinically normal dogs and 14 dogs with pyoderma following oral administration of the drug at 7.5 mg/kg once daily for 5 to 7 days. Skin biopsies and whole blood samples were obtained before dosing and at the time of the expected maximum concentration in skin (3 hours after dosing) on the first and on the fifth to seventh day of dosing. Skin biopsies and plasma were analyzed for orbifloxacin concentrations by high-performance liquid chromatography. Dogs with pyoderma had significantly higher mean skin concentrations of orbifloxacin within 3 hours of administration (Day 0: 7.80 +/- 3.40 mcg/g, Days 4 to 6: 9.47 +/- 6.23 mcg/g) than did dogs with normal skin (Day 0: 3.85 +/- 1.08 mcg/g, Days 4 to 6: 5.43 +/- 1.02 mcg/g). After dosing on Day 0 and after five to seven daily treatments, dogs with pyoderma had significantly higher mean orbifloxacin skin:plasma ratios (1.40 and 1.44, respectively) than did clinically normal dogs (0.81 and 0.96, respectively). The accumulation of orbifloxacin in diseased skin may contribute to the efficacy of this compound for the treatment of bacterial skin infections.

4065 Background: Cetuximab is a chimeric IgG1 Mab that targets the human epidermal growth factor receptor (EGFR). Most clinical trials using cetuximab in mCRC treated patients (pts) with EGFR posit...

14617 Background: Platelet derived growth factor receptor alpha (PDGFRα) plays a critical role in tumorigenesis and tumor progression. PDGFRα and its ligands are expressed by an array of tumors and...